The present invention is generally related to diazapane compounds and more particularly to substituted diazapane compounds showing utility as antagonists of Neurokinin 1 Receptors.
The neuropeptide receptors for substance P (NK-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes.
The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214) and anxiety (Can., J. Phys., 1997, 75, 612-621).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases reviewed in xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993.
The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in xe2x80x9cNeuropeptides, 32(1), 1-49, (1998)xe2x80x9d and xe2x80x9cEur. J. Pharmacol., 383(3), 297-303, (1999)xe2x80x9d.
Furthermore, neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in xe2x80x9cNeuropeptides, 32(1), 1-49, (1998)xe2x80x9d and xe2x80x9cEur. J. Pharmacol., 383(3), 297-303, (1999)xe2x80x9d.
NK1 receptor antagonists have been reported to have also a beneficial effect in the therapy of traumatic brain injury (oral disclosure by Prof. Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, Oct. 17-20, 2000 with the title xe2x80x9cNeurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injuryxe2x80x9d (Authors: A. J. Nimmo, C. J. Bennett, X.Hu, I. Cemak, R. Vink).xe2x80x9d
The present invention provides a compound of the formula 
wherein
R1, R2 are independently from each other aryl or heteroaryl, wherein the heteroaryl group contains one or two heteroatoms, selected from N, O or S, and wherein the aryl or heteroaryl groups are unsubstituted or substituted by 1 to 3 substituents, which are independently from each other halogen, CF3, lower alkoxy or lower alkyl;
R3 is hydrogen, lower alkyl, xe2x80x94(CH2)nN(R)2, xe2x80x94(CH2)n-heteroaryl or is a xe2x80x94(CH2)n-non aromatic heterocycle, the heterocycles are unsubstituted, or substituted by halogen, CF3, lower alkoxy or lower alkyl;
R4 is xe2x95x90O, xe2x95x90N(CH2)nCH3 or xe2x95x90N(CH2)nN(R)2, or wherein R3 and R4 together with the N and C atoms to which they are attached, form the group xe2x80x94CR5xe2x95x90Nxe2x80x94Nxe2x95x90;
R5 is hydrogen, xe2x80x94(CH2)nN(R)2, xe2x80x94(CH2)n-heteroaryl or is a xe2x80x94(CH2)n-non aromatic heterocycle, which heterocycles are unsubstituted, or, substituted by halogen, CF3, lower alkoxy or lower alkyl;
R is hydrogen or lower alkyl;
n is 0, 1, 2 or 3;
and pharmaceutically acceptable acid addition salts and their enantiomers.
The compound of formula I and pharmaceutically acceptable salts thereof are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
The compounds of formula I can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compounds advantages in adsorption, pharmacokinetics in distribution and transport to the brain.
Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts and their enatiomeric forms thereof, the preparation of the above-mentioned compounds, pharmaceutical compositions containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.
The present invention is a compound of the stucture 
wherein
R1 and R2, are a substituted or unsubstituted aryl ring structure having six to twelve carbon ring atoms, or a substituted or unsubstituted heteroaryl ring structure having five to twelve ring members with one or two of the ring members being a heteroatom selected from the group consisting of nitrogen, oxygen or sulfur. The substituted aryl or heteroaryl ring structure is substituted with one to three substituents selected from the group consisting of halogen, CF3, lower alkoxy, and lower alkyl.
R3 is independently hydrogen, lower alkyl, xe2x80x94(CH2)nN(R)2, xe2x80x94(CH2)nxe2x80x94Xxe2x80x94;
R4 is independently xe2x95x90O, xe2x95x90N(CH2)nCH3 or xe2x95x90N(CH2)nNR2, or taken together with R3 and with their respective attached N and C atoms form xe2x80x94CR5xe2x95x90Nxe2x95x90Nxe2x80x94;
R5 is hydrogen, xe2x80x94(CH2)nN(R)2 or is a substituted or unsubstituted xe2x80x94(CH2)nxe2x80x94X;
X is a substituted or unsubstituted heterocyclic ring structure having five to twelve ring members, with one or two of the ring members being a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen. The substituted heterocyclic ring structure being substituted with one to three substituents selected from the group consisting of halogen, CF3, lower alkoxy, and lower alkyl;
R is hydrogen or lower alkyl; and
n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt and enantiomeric forms thereof.
Preferred embodiments of compound I include a compound of structure of I-a 
In one preferred embodiment of compound 1-a, R3 is hydrogen, R1 is an aryl ring structure, such as a substituted phenyl ring structure, and R2 is a substituted ring structure. In another preferred embodiment, R3 and R1 are as above, and R2 is a substituted napthyl ring structure. In yet another preferred embodiment of compound 1-a, R1 is a heteroaromatic ring structure, R2 is a substituted phenyl ring structure and R3 is hydrogen. A further preferred embodiment of compound 1-a includes R1 and R2 as substituted or unsubstituted aromatic ring structures and R3 is a non-aromatic heterocyclic ring structure. Yet another preferred embodiment of compound 1-a has R1 and R2 as substituted or unsubstituted aromatic ring structures, and R3 as an aromatic heterocycle. In a further preferred embodiment of compound 1-a, R1 and R2 are substituted or unsubstituted aromatic ring structures, and R3 is amino alkyl or lower alkyl.
Another preferred embodiment of compound 1 has the structure 
1-b, wherein R1 and R1 are substituted or unsubstituted ring structures. A preferred embodiment of compound 1-b includes a compound with R5 as hydrogen. Another preferred embodiment of compound 1-b includes R5 as a non-aromatic heterocyclic ring. Yet another preferred embodiment of compound 1-b includes R5 as amino alkyl.
Yet another preferred embodiment of compound 1 has the structure 
1-c wherein R1 and R2 are substituted or unsubstituted aromatic ring structures and R3 is hydrogen.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9carylxe2x80x9d denotes, for example, phenyl or naphthyl, which may be optionally substituted by one to three substituents, for example by halogen, trifluoromethyl, lower alkyl or lower alkoxy.
The term xe2x80x9cheteroarylxe2x80x9d denotes, for example, the following heterocycles: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indazolyl, indolyl, pyrazolyl, benzothienyl, thienyl, furyl, pyrrolyl, imidazolyl, isoquinolyl, isothiazolyl or quinolinyl. Preferred are pyridyl, quinolinyl, indolyl, benzothienyl and pyrazolyl.
The term xe2x80x9cnon aromatic heterocyclexe2x80x9d denotes, for example the following groups: morpholinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl and piperazinyl. Preferred groups are morpholinyl and piperidinyl.
In the reaction schemes below, the symbols 
indicate a solid phase resin such as beta-alanine-NH2-WANG resin and the like.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Exemplary preferred are compounds, in which R4 is an oxo group and R1 and R2 are both aryl, for example the following compounds:
(3S)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-[1,4]diazepane-2,5-dione,
(3S)-3-(3,4-dichloro-benzyl)-1-(2-methoxy-naphthalen-1-yl-methyl)-[1,4]diazepane-2,5-dione,
(3S)-3-(3,4-dichloro-benzyl)-1-(2-methyl-naphthalen-1-yl-methyl)-[1,4]diazepane-2,5-dione,
3-(3,4-dichloro-benzyl)-1-(2-ethoxy-naphthalen-1-yl-methyl)-[1,4]diazepane-2,5-dione,
(RS)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-5-propylimino-[1,4]diazepan-2-one hydrochloride and
(RS)-3-(3,4-dichloro-benzyl)-1-(2-methoxy-naphthalen-1-yl-methyl)-4-pyridin-3-ylmethyl-[1,4]diazepane-2,5-dione.
Further preferred are compounds, in which R4 is an oxo group and one of R1 or R2 is aryl and the other is heteroaryl.
An example of such compound is:
(3S)-3-(1H-indol-3-yl-methyl)-1-(2-methoxy-naphthalen-1-ylmethyl)-[1,4]diazepane-2,5-dione.
Preferred are further compounds, in which R4 is an oxo group and R1 and R2 are both heteroaryl, for example the following compound:
(3S)-1-(2,8-bis-trifluoromethyl-quinolin-4-yl-methyl)-3-(1H-indol-3-ylmethyl)-[1,4]diazepane-2,5-dione.
Further preferred are compounds, in which R3 and R4 are together with the N and C atom to which they are attached the group xe2x80x94CR5xe2x95x90Nxe2x80x94Nxe2x95x90 and R5 has the meaning described above.
Examples of such compounds are:
(4S)-4-(3,4-dichloro-benzyl)-6-(2-methoxy-naphthalen-1-yl-methyl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one,
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one,
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-(2-morpholin-4-yl-ethyl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one,
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-piperidin-1-yl-methyl-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one,
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-dimethylaminomethyl-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one,
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-(1-methyl-piperidin-2-yl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one and
(RS)-4-(3,4-dichloro-benzyl)-6-naphthalen-1-yl-methyl-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) cyclizing a compound of formula 
to give a compound of formula 
wherein R1 and R2 have the significances given above, or
reacting a compound of formula 
with a compound of formula
R3xe2x80x94Xxe2x80x83xe2x80x83II 
to a compound of formula 
wherein R1 to R3 have the significances given above and X is halogen, or
cyclizing a compound of formula 
to give a compound of formula 
wherein R1 and R2 have the significances given above, or
reacting a compound of formula 
with a compound of formula
R6xe2x80x94NH2xe2x80x83xe2x80x83V 
to a compound of formula 
wherein R6 is xe2x80x94(CH2)nCH3 or xe2x80x94(CH2)nN(R)2 and R1, R2, n and R are given above, or
reacting a compound of formula 
with a compound of formula
R5xe2x80x94COxc2x7Nxe2x80x94NH2xe2x80x83xe2x80x83VI 
to a compound of formula 
wherein the definitions of substituents are given above, or
cyclizing a compound of formula 
to a compound of formula 
wherein R3xe2x80x2 is lower alkyl, xe2x80x94(CH2)n-1N(R)2, xe2x80x94(CH2)n-1-heteroaryl or is a xe2x80x94(CH2)n-1-non aromatic heterocycle, which heterocycles are optionally substituted by halogen, CF3, lower alkoxy or lower alkyl; and R1 and R2 are described above, or
modifying one or more substituents R1-R3 within the definitions given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt or into its enantiomeric form.
The following schemes 1-4 describe the processes for preparation of compounds of formula I in more detail. The starting materials are known compounds or may be prepared according to methods known in the art.
In the schemes the following abbreviations have been used:
BOP-Cl bis-(2-oxo-3-oxazolidinyl)phosphinic chloride
DDC N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide
NMM N-methylmorpholine
DIPEA N-ethyldiisopropyl-amine
TFA trifluoroacetic acid
HOBT 1-hydroxy-benzotriazole
DIC diisopropylcarbodiimide
Fmoc [(9H-fluoren-9-ylmethoxy)carbonyl]
HOAt 1-hydroxy-7-azabenzotriazole 
The definition of substituents is described above. 
The substituents are described above. 
R1, R2 and R5 are described above and R6 is xe2x80x94(CH2)nCH3 or xe2x80x94(CH2)nN(R)2 and R is hydrogen or lower alkyl and n is 0 to 3. 
R1 and R2 are described above and R3xe2x80x2 is lower alkyl, xe2x80x94(CH2)n-1N(R)2, xe2x80x94(CH2)n-1-heteroaryl or is a xe2x80x94(CH2)n-1-non aromatic heterocycle, which heterocycles are optionally substituted by halogen, CF3, lower alkoxy or lower alkyl;
In accordance with scheme 1 compounds of examples 1 to 5 and 8 to 18 have been prepared as follows:
A compound of formula IX, wherein R2 is, for example, 3,5-trifluoromethylphenyl, naphthalen-1-yl, 4-chloro-3-(trifluoromethyl)-phenyl, 2-methoxy-naphthalen-1-yl, 2-methyl-naphthalen-1-yl or 2-ethoxy-naphthalen-1-yl, is added to an ethanolic solution of tert.-butylacrylate of formula VIII at about 70xc2x0 C. The obtained liquid is further solved in a solution, containing a compound of formula XIII, wherein R1 may be, for example 3,4-dichlorophenyl, benzo[b]thiophen-3-yl, 4-chlorophenyl, 3-chlorophenyl, indol-3-yl or 2,4,5-trichloro-phenyl, and N-methylmorpholine (NMM) and bis-(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) in dichloromethane. The mixture is stirred for about 2 h at room temperature. After drying, to the residue is added NMM, N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide (EDC), 1-hydroxy-benzotriazole ((HOBT) and N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide (EDC) to obtain a compound of formula I-1.
Further in accordance with scheme 1, the hydrogen atom of compounds of formula I-1 may be replaced by the substituent R3, which process is described in examples 13 and 14 as follows: To a solution of a compound of formula I-1 in DMF is added a sodium hydride suspension in mineral oil at room temperature under argon. Then, a compound of formula II, for example methyliodide or 4-(2-chloroethyl)-morpholine is added to obtain a compound of formula I-2.
In accordance with scheme 1, a compound of formula X may further be obtained by processes, described in examples 2a, 3 and 8. A compound of formula XI, for example 2-methoxynaphthaldehyde, 2,8-bis(trifluoromethyl)-4-quinoline carboxaldehyde or 4-methoxynaphthaldehyde is solved in dichloromethane. To the cooled (0xc2x0 C.) solution is added sodium borohydride and it is stirred for about 1 h. The residue is purified to give a compound of formula X.
In accordance with scheme 2, examples 6 and 7 are prepared. These processes are solid phase synthesis. A slurry of beta-alaninexe2x80x94NH2xe2x80x94WANG resin in dichloromethane is treated with a compound of formula XI, for example with 1-naphthyldehyde or with bis-3,5-trifluoromethyl-benzylaldehyde, and with sodium triacetatoxyborohydride. The resin is washed with tetrahydrofurane, water, aqueous 10% sodium hydrogencarbonate solution and dichloromethane. A slurry of this resin is allowed to swell to about 30 min. Then 1-hydroxy-7-azabenzotriazole, diisopropyl-carbodiimide (DIC), N[(9H-fluoren-9-ylmethoxy)carbonyl]-L-triptophan (Fmoc-L-triptophan) and diisopropylethylamine are added. After the resin was washed, the N-protecting group is removed by adding a solution of piperidine in dimethylformamide at room temperatur. Then the resin is stirred for about 30 min in a mixture of trifluoroacetic acid (TFA) and dichloromethane. After concentration of the organic layers and an azeotropical dry, diisopropylethylamine (DIPEA), DIC and 4-dimethylamine-pyridine are added. The mixture is stirred and the volatiles are removed. A compound of formule I-1 is obtained.
Scheme 3 describes the preparation of compounds of formula I-3 and 1-4, specifically described in examples 19 to 27. In accordance with scheme 3, a compound of formula I-1, for example
(3S)-3-(3,4-dichloro-benzyl)-1-(2-methoxy-naphthalen-1-ylmethyl)-[1,4]diazepan-2,5-dione, (RS)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-[1,4]diazepan-2,5-dione or (RS)-3-(3,4-dichloro-benzyl)-l -(naphthalen-1-ylmethyl)-[1,4]diazepan-2,5-dione, is solved in dimethylformamide and then a suspension of sodium hydride in mineral oil is added at room temperature. After forming a clear solution, bis(dimethylamino)phosphorochloridate (IV) is added. The reaction mixture is stirred and then a corresponding hydrazine of formula VI is added to give a compound of formula I-4.
An alternative method to obtain a compound of formula I-4 is the reaction of a compound of formula I-1 with the Lawesson""s reagent. Lawesson""s reagent is 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide. The obtained dithioamide was separated by column chromatography and the corresponding hydrazide is added as described above to obtain the desired compound of formula I-4.
Further, in accordance with scheme 3, a compound of formula I-3 is obtained by reacting a compound of formula IV with an amine derivative of formula V. R6 in formula V are
xe2x80x94(CH2)nCH3 or the group xe2x80x94CH2)nN(R)2 and R is lower alkyl or hydrogen and n is 0 to 3. The reaction is carried out at about 50xc2x0 C.
In accordance with reaction scheme 4 a compound of formula I-5 is obtained. The process steps are described in more detail in examples 28 to 36. A compound of formula XXI, for example 9-fluoremethyloxycarbonyl-L-3,4-dichlorophenylalanine is suspended in a solution of dichloromethane, NMM and BOP-Cl. Then a compound of formula X, for example 3-(3,5-bis-trifluoromethylbenzylamino)-propionic acid tert.-butyl ester is added to give a compound of formula XXII. To a solution of a compound of formula XXII in 1,2-dichloroethane is added a corresponding aldehyde in the presence of sodium triacetoxy-borohydride to give a compound of formula VII, which is then cyclized with TFA, NMM, EDC and HOBT to the corresponding compounds of formula I-5.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids came into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The compounds were investigated in accordance with the tests given hereinafter. All of the compounds listed as examples below were active in the following assay. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue.
The affinity of test compounds for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04 %) leupeptin (8 xcexcg/ml), MnCl2 (3 mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of [3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3 %) with 2xc3x972 ml washed of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The affinity to the NK-1 receptor, given as pKi, is in the scope of 8.00-9.00 for the preferred compounds.
In the table below are shown some specific activity data of preferred compounds:
The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragxc3xa9es and hard gelatine capsules.
Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
The following Examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.